Baseline Characteristics and Effects of Growth Hormone Therapy over Two
Years in Younger and Elderly Adults with Adult Onset GH Deficiency
Celina Franco, Gudmundur Johannsson, Bengt-Åke Bengtsson, Johan Svensson
Research Centre for Endocrinology and Metabolism, Gröna Stråket 8, Sahlgrenska
University Hospital, SE-413 45 Göteborg, Sweden
Short title: GH replacement in elderly GHD patients
Key words: Elderly, growth hormone deficiency, body composition, bone mass,
glucose homeostasis, serum lipid pattern
Disclosure statement: The authors have nothing to disclose
Number of words (text): 3600
Number of words (abstract): 250
Number of tables: 4
Number of figures: 2
Correspondence to:
Johan Svensson, M.D.
Research Centre for Endocrinology and Metabolism
Gröna Stråket 8
Sahlgrenska University Hospital
SE-413 45 Göteborg
Seweden
Tel:+46 31 7411712
Fax:+46 31 821524
E-mail: Johan.Svensson@medic.gu.se
J Clin Endocrin Metab. First published ahead of print August 29, 2006 as doi:10.1210/jc.2006-0887
Copyright (C) 2006 by The Endocrine Society
Years in Younger and Elderly Adults with Adult Onset GH Deficiency
Celina Franco, Gudmundur Johannsson, Bengt-Åke Bengtsson, Johan Svensson
Research Centre for Endocrinology and Metabolism, Gröna Stråket 8, Sahlgrenska
University Hospital, SE-413 45 Göteborg, Sweden
Short title: GH replacement in elderly GHD patients
Key words: Elderly, growth hormone deficiency, body composition, bone mass,
glucose homeostasis, serum lipid pattern
Disclosure statement: The authors have nothing to disclose
Number of words (text): 3600
Number of words (abstract): 250
Number of tables: 4
Number of figures: 2
Correspondence to:
Johan Svensson, M.D.
Research Centre for Endocrinology and Metabolism
Gröna Stråket 8
Sahlgrenska University Hospital
SE-413 45 Göteborg
Seweden
Tel:+46 31 7411712
Fax:+46 31 821524
E-mail: Johan.Svensson@medic.gu.se
J Clin Endocrin Metab. First published ahead of print August 29, 2006 as doi:10.1210/jc.2006-0887
Copyright (C) 2006 by The Endocrine Society
Abstract
Context: The effects of GH replacement in elderly GH deficient (GHD) adults are not well known.
Objective/Design/Patients: In this prospective, single-centre, open-label study, baseline characteristics and the effects of 2-year GH replacement were determined in 24 GHD adults above 65 years of age and in 24 younger GHD patients (mean age
37; range 27-46 years). All patients had adult onset disease and both groups were comparable in terms of number of pituitary hormonal deficiencies, gender, body mass index (BMI), and waist:hip ratio. Duration of hypopituitarism was, however, longer in
the elderly patients.
Results: The mean maintenance dose of GH was 0.31 (SEM 0.03) mg/day in the elderly GHD patients and 0.44 (0.04) mg/day in the younger patients. The less marked response in IGF-I SD score, total body fat and extracellular water in the elderly patients lost significance when the dose of GH were accounted for in the statistical analyses. In spite of the lower dose in the elderly GHD group, these patients had a more marked reduction in waist:hip ratio and serum low density lipoprotein-cholesterol (LDL-C) level, and these differences remained also after correction for duration of hypopituitarism. There was no difference at baseline or in responsiveness in lean mass, bone mineral density and glucose homeostasis.
Conclusions: This study identifies elderly GHD adults as a GH sensitive group in whom a low dose of GH can improve body composition and serum lipid profile without any significant impairment of glucose metabolism. GH replacement should therefore be considered in elderly GHD adults.
Introduction
Growth hormone (GH) secretion declines with increasing age (1, 2). This may be important for the metabolic changes seen in normal aging, such as an increased relative amount of total and visceral fat, and increased low density lipoproteincholesterol (LDL-C) (1, 2). There are, however, distinct differences between normal elderly subjects and elderly GH deficient (GHD) adults with structural hypothalamicpituitary disease. The elderly GHD adults have lower GH secretion (3) and increased total body fat (4) as compared with age-matched healthy subjects whereas there is little difference in lean mass (4) and bone mass (5, 6). GH replacement can normalize most features of adult GHD (7-9). The response to GH replacement may, however, vary in different subgroups of patients depending on the cause and severity of disease (10), as well as on whether the disease was acquired in childhood or adulthood (11). Little is known of the responsiveness to GH replacement in elderly GHD adults. Several studies suggest that GH replacement in elderly GHD patients has similar efficacy as in younger GHD adults in terms of body composition and serum lipid pattern (12, 13), but it is unknown if the magnitude of the changes differs. It has been suggested in some studies that the elderly GHD patients may need a lower dose of GH than younger patients (14) whereas in other studies, it has been suggested that the main effect of GH replacement in elderly patients may be to prevent further age-related decline in variables such as muscle strength (15). In this single-center, prospective study, baseline characteristics were determined in 24 consecutive GHD patients > 65 years of age at study start and compared with those in 24 GHD adults aged 27-46 years. The two groups were matched with regard to gender, BMI, waist circumference, waist/hip ratio, and number of anterior pituitary hormonal deficiencies, and all patients had adult onset GHD. The main purpose was to study between-group differences in the response to 2-year GH replacement therapy in body composition, bone mass, and metabolic indices.
Patients and Methods
Patients: Twenty-four consecutive GHD adults > 65 years of age (mean age 68, range 65-75 years) and 24 younger GHD adults (age 37, range 27-46 years) were included 1992-1997. All patients had adult onset pituitary disease (Table 1). No patient had previously received GH treatment. In both study groups, 20 patients had been treated surgically. Nine and 6 patients had received radiotherapy in the elderly and in the younger patients, respectively. In 44 of the patients, the diagnosis of GHD was based on a peak GH < 3 µg/L during a stimulation test [insulin (n=41), GHRH (n=3), glucagon (n=1)]. In one elderly patient and in two younger patients, all with multiple pituitary hormonal deficiencies, the diagnosis was based on measurements of 24-hour spontaneous GH secretion (n=2) or on a serum IGF-I concentration below - 2 SD (n=1). When required, patients received adequate and stable therapy with glucocorticoids, thyroid hormone, gonadal steroids and desmopressin. However, at entry to the study, 2/9 (22%), and 5/9 (56%) of the estrogen deficient women in the elderly and younger GHD groups, respectively, received estrogen therapy. In 5 patients, GH replacement was discontinued during the study period. Three of these patients were elderly patients [fatal myocardial infarction (n=1), prostate cancer (n=1, this patients had urinary symptoms already before GH replacement was initiated), and lack of compliance (n=1)]. One patient in the younger group discontinued GH replacement due to reoccurrence of pituitary tumor and one patient was lost to follow-up as this patient moved to another part of Sweden. Patients who discontinued GH replacement were, however, retained in the statistical analysis according to the intention-to treat approach used.
Study protocol: This is an ongoing, prospective, open label treatment trial in adult GHD patients. Various brands of recombinant human GH are used in this trial. In 2 patients (one elderly and one younger patient), the initial target dose of GH was 11.9 µg/kg/d (0.25 IU/kg/week). The dose in these 2 patients was gradually lowered and individualized already during the first year of treatment. In the remaining 46 patients, the dose of GH was individualized from the beginning (16). The individualization of the dose of GH was performed with the aim of normalizing IGF-I SD score (target range: 0 - + 2 SD of predicted values) and body composition (to approximately 100% of predicted values as estimated by the four-compartment model) in each patient (16). The use of IGF-I SD scores may result in lower absolute serum IGF-I values in the elderly than in the younger GHD patients during the GH replacement as serum IGF-I concentration declines with increasing age in the normal population (17). In most patients, the titration of the dose of GH was based on the IGF-I SD score. However, in some patients, mainly patients with an IGF-I SD score in the low normal range at baseline, the normalization of body composition was of increasing importance. The initial dose of GH was 0.5 - 1.0 IU (0.17 - 0.33 mg) per day in the patients that received individualized dose titration. Dose adjustments were made by 0.1 - 0.17 mg per day dependent on the injection device being used. According to the study protocol, the dose of GH was to be reduced by half in the event of side-effects that became a burden for the patients. Therefore, the dose of GH was reduced by half due to fluid-related side-effects in the two patients (one elderly and one young GHD patient) that received their initial dose of GH based on body weight. Smaller reductions (0.1-0.17 mg per day) of the dose of GH were made in 14 additional patients (5 elderly and 9 young patients) due to IGF-I SD score values above + 2 SD or due to mild fluid-related side-effects.
At baseline and then after each year of GH treatment, physical and laboratory examinations were performed including measurements of body composition, bone mass, and metabolic indices. Dose titration and safety monitoring were performed every third month during the first year and every sixth month thereafter. Body weight was measured in the morning to the nearest 0.1 kg, and body height was measured barefoot to the nearest 0.01 m. Body mass index (BMI) was calculated as the weight in kilograms divided by the height in meters squared. Waist circumference was measured in the standing position with a flexible plastic tape placed midway between the lower rib margin and the iliac crest, and hip girth was measured at the widest part of the hip. Systolic and diastolic blood pressure were measured after at least 5 minutes of supine rest using the sphygmomanometric cuff method. No effort was made to influence the patients physical activity level during the study period.
Ethical considerations: Informed consent was obtained from all patients. The study was approved by the Ethics Committee at the University of Göteborg and the Swedish Medical Products Agency (Uppsala, Sweden).
Body composition: Dual-energy X-ray absorptiometry (DEXA) (Lunar DPX-L, Lunar Corporation, Madison, Wisconsin, USA; software version 1.3) was used to measure lean body mass (LBM) and body fat (BFDEXA) (18). The relative error for LBM was 1.5%. Body cell mass (BCM), extra cellular water (ECW), and body fat (BF) were estimated using a four-compartment model based on total body potassium (TBK) and total body water (TBW) assessments (19). TBK was assessed using a whole body counter [coefficient of variation (CV) = 2.2%] and TBW was determined by the isotope dilution of tritiated water (CV = 3.2%). Normative values were derived from studies of 476 healthy subjects (19). Individual observed/predicted values ratios could then be calculated for BCM (BCM%), ECW (ECW%) and BF (BF%).
BMC and BMD DEXA (Lunar DPX-L, software version 1.3) was used to measure BMC and BMD (18). A calibration phantom (COMAC-BME Quantitative Assessment of Osteoporosis Study Group) was used. The CVs between measurements were 0.4%, 0.5%, and 0.6% for total body, lumbar (L2-L4) spine, and femur neck BMD. BMD z-score, which is the difference in SD of age- and sex-matched healthy subjects, and t-score, which is the difference in SD of sex-matched young (20-39-yr-old) healthy subjects, were determined using the Lunar DPX-L software program.
Biochemical assays: Serum IGF-I concentration was determined by a hydrochloric acid-ethanol extraction radioimmunoassay (RIA) (Nichols Institute Diagnostics, San Juan Capistrano, CA). Inter-assay and intra-assay CVs were 5.4 and 6.9%, respectively, at a mean serum IGF-I level of 126 µg/L, and 4.6 and 4.7%, respectively, at mean serum IGF-I level of 327 µg/L. The individual serum IGF-I values were compared with age- and sexadjusted values obtained from a reference population of 197 men and 195 women (17). The individual IGF-I SD scores could then be calculated (20). Serum osteocalcin was measured by a double-antibody RIA (International CIS, GiFsur Yvette, France) with inter-assay and intra-assay CVs of 2.4 and 2.9%, respectively, at a serum concentration of 10.4 ug/L, and 3.3 and 2.9%, respectively, at a mean serum concentration of 22.3 ug/L. Serum calcium was measured by absorption spectrophotometry (Boehringer Mannheim, Mannheim, Germany) with an inter-assay CV of 2.5% and an intra-assay CV of 1.7%. Intact PTH was measured by immunoradiometric assay (Nichols Institute Diagnostics) with inter-assay and intra8 assay CVs of 7.8 and 7.4% at a mean serum concentration of 23.4 ng/L, and 6.0% and 4.5%, respectively, at serum concentration of 43.1 ng/L. Total cholesterol (TC) and triglyceride (TG) concentrations were determined using enzymatic methods (Boehringer Mannheim). The inter-assay CVs for TC and TG determinations were 2.9% and 3.8%, respectively, and intra-assay CVs were 0.9% and 1.1%, respectively. High density lipoprotein (HDL-C) levels were determined after the precipitation of apolipoprotein B - containing lipoproteins with MgCl2 and heparin (21). Low density lipoprotein cholesterol (LDL-C) was calculated according to Friedewald's formula adjusted to SI units (22). Serum insulin was determined by RIA (Phadebas, Pharmacia, Sweden) and blood glucose was measured with the glucose-6-phosphate dehydrogenase method (Kebo Lab, Stockholm, Sweden). Serum HbA1c was determined by high-pressure liquid chromatography (Waters, Millipore AB, Sweden).
Statistical methods
All the descriptive statistical results are presented as the mean and SEM. Betweengroup differences during the 2-year treatment period were determined using a oneway analysis of variance (ANOVA) of the percent change from baseline at all time points, and with onset category as the independent variable. Between-group p-values at baseline and at study end were determined using one-way ANOVA. Within-group p-values were determined using a one-way ANOVA followed by Student-Newman-Keuls post hoc test. All analyses were performed according to the intention-to-treat principle (using the carry forward principle). A two-tailed P < 0.05 was considered significant.
Results
Baseline characteristics (Table 1) Both study groups consisted of 15 men and 9 women (Table 1). The two groups were comparable in terms of gender, body length, body weight, BMI, waist circumference, waist:hip ratio, and number of anterior pituitary hormonal deficiencies (Table 1). There was, however, a non-significant tendency for the younger GHD patients to be taller and heavier and that the elderly patients had larger waist:hip ratios. Furthermore, duration of hypopituitarism was longer in the elderly GHD group (Table 1). GH dose and serum IGF-I (Fig. 1) The daily dose of GH was lower in the elderly GHD patients throughout the 2-year follow-up (Fig. 1A). Serum IGF-I level was lower in the elderly patients throughout treatment (Fig 1B). The serum IGF-I SD score (adjustment for age and gender) tended, however, to be higher in the elderly GHD adults (p=0.16) at baseline (Fig. 1C). There was no significant between-group difference in the percent change in absolute serum IGF-I level whereas the change in IGF-I SD score was smaller in the elderly than in the younger GHD adults (Fig. 1). BMI, waist; hip ratio and blood pressure (Table 2) There was no change during the study period in either group in body weight. Waist circumference and waist:hip ratio reduced more markedly in the elderly GHD group. Systolic and diastolic blood pressures were higher in the elderly GHD group throughout treatment. Although transient reductions in systolic and diastolic blood pressure were observed in the elderly GHD patients after one year of treatment, there was no significant between-group difference.
Body composition (Table 3 and Fig. 2) At baseline, there was no difference in absolute values of measures of body composition except for a lower body cell mass, as measured using the fourcompartment model, in the elderly GHD patients (Table 3). If body composition values were expressed as a percentage of body weight, however, baseline fat and lean mass (including body cell mass) were similar in the two study groups (data not shown). After correction for age and gender using observed/predicted values ratios (four-compartment model), the elderly GHD patients had lower baseline body fat (% of predicted) than the younger GHD patients (Fig 2). The responsiveness to GH replacement in fat and lean mass, both in terms of absolute values (Table 3) or percentages of body weight (data not shown), was similar in the two groups. Body fat (observed/predicted values ratios) was, however, less affected by GH replacement in the elderly GHD patients (Fig. 2). Extracellular water, both expressed as absolute values and as observed/predicted values ratios, was less affected by treatment in the elderly GHD adults (Table 3 and Fig. 2).
Bone markers, BMC, and BMD (data not shown) There was no baseline difference in circulating markers of bone turnover (osteocalcin, calcium, and intact PTH). Within both study groups, circulating osteocalcin and calcium levels were increased by the GH replacement whereas serum intact PTH level was unaffected within both groups. There was, however, no between-group difference in the response to treatment (data not shown). Baseline total body or lumbar (L2-L4) spine BMC, BMD, t-score and z-score was not statistically different between the two groups (data not shown). There was, however, non-significant tendencies to lower total body BMD [1.15 (0.03) vs. 1.20 (0.02) g/cm2], lumbar (L2-L4) spine BMD [1.08 (0.07) vs. 1.18 (0.03) g/cm2], and total body and lumbar (L2-L4) spine t-scores (not shown) in the elderly than in the younger patients. Total body and lumbar (L2-L4) spine z-scores, however, tended to be higher in the elderly GHD patients and were approximately that predicted in the background population (z-score ˜ 0) in this group [mean (SEM) total body and lumbar (L2-L4) spine z-scores in the elderly GHD group were -0.02 (0.24) and 0.06 (0.26), respectively, both p=N.S. vs. the young group]. At the femur neck, BMC [4.46 (0.33) vs. 5.31 (0.18) g; p<0.05], BMD [0.84 (0.05) vs. 1.02 (0.02) g/cm2; p<0.001], and tscore (data not shown, p<0.001) were lower in the elderly than in the younger patients, whereas there was a weak tendency to higher femur neck z-score in the elderly than in the younger GHD group [-0.07 (0.22) vs. -0.21 (0.16); p=N.S.]. There was no within- or between-group difference in the response to 2-year GH replacement in any variable reflecting bone mass and density.
Metabolic analyses (Table 4) At baseline, serum LDL-C concentrations were higher in the elderly GHD adults whereas circulating levels of TC, HDL-C, TG, glucose, insulin, and HbA1c were similar in both groups. A reduction in serum LDL-C level, and a tendency to a reduction in serum TC level, were only found in the elderly GHD adults (p<0.05 and p=0.05, respectively, vs. younger GHD group). There were no within- or betweengroup changes in the other measured metabolic indices.
Analysis of covariance: When the higher dose of GH in the younger GHD patients were accounted for using analysis of covariance, the between-group differences in responsiveness in terms of IGF-I SD score, BF% , ECW, and ECW% lost statistical significance. The more marked reductions in the elderly GHD group in waist:hip ratio, waist circumference and serum LDL-C level all remained also after correction for the longer duration of hypopituitarism in the elderly patients (p<0.05, p<0.01 and p<0.05, respectively).
Discussion
In this single-center, prospective study, a low mean dose of GH normalized serum IGF-I concentration and improved body composition in elderly GHD patients without any significant deterioration in glucose homeostasis. The reductions in waist:hip ratio and serum LDL-C concentration were even more marked in the elderly GHD patients than in the younger GHD patients. Therefore, low-dose GH replacement therapy produces beneficial effects also in elderly GHD adults.
In this study, only one patient in each group started GH replacement with a fix dose of GH based on body weight and already within the first year of treatment, the dose was gradually individualized in these two patients. In all other patients, the GH therapy was individualized from study start. Therefore, the results of this study show, in line with some previous observations (14), that individualized GH replacement results in a lower dose of GH in elderly than in younger GHD patients. Furthermore, the elderly GHD patients had lower absolute values of serum IGF-I at baseline than the younger GHD patients whereas after correction for the age-related decline in serum IGF-I concentration using IGF-SD score, there was a non-significant tendency to higher IGF-I SD score in the elderly patients. This confirms previous observations of a greater overlap in serum IGF-I level between GHD adults and normal individuals with increasing age (23). The change in IGF-I SD score in response to GH was less marked in the elderly GHD adults. Although IGF-I SD score was statistically similar in the two study groups after one and two years, the IGF-I SD score values at these timepoints were approximately + 2 SD in the young GHD patients. This, combined with the supranormalization of extracellular water in the younger patients, could suggest that the dose of GH was a little too high in this group.
The between-group differences at baseline were not due to differences in gender distribution, BMI or severity of disease (as estimated by number of anterior pituitary hormonal deficiencies), since the two study groups were comparable with regard to these factors. However, although they had similar BMI, the elderly patients tended to have higher waist circumference and waist:hip ratios. Baseline total body fat (observed/predicted values ratio), was, however, lower in the elderly than in the younger patients. These results demonstrate that the younger subjects had more excess body fat than the elderly whereas the elderly patients had a more marked abdominal/visceral fat distribution. This is not surprising since visceral obesity increases with ageing in the normal population and therefore, increasing age possibly increases the relative amount of abdominal/visceral obesity also in GHD adults. In the elderly GHD patients, body cell mass was approximately that predicted in the background population, which supports previous observations that there is no major abnormality in lean mass in elderly GHD adults (4).
As measured using the four-compartment model, the reduction of body fat (observed/predicted values ratio), and the increase in extracellular water, were less marked in the elderly GHD patients after 2-year GH replacement. After correction for the lower dose of GH in the elderly patients using an analysis of covariance, the difference in responsiveness in total body fat and extracellular water lost statistical significance. This suggests that GH dose-dependently decreased body fat and increased extracellular water in GHD adults independent of age, thereby eliminating the baseline difference in body fat between the two study groups. Extracellular water, was, however, increased to supraphysiological levels in the younger patients, which is in line with a previous report of more marked fluid retention in younger GHD adults in response to GH replacement (14).
At baseline, serum LDL-C level was, as in the normal population, higher in the elderly than in the younger GHD patients. This suggests, as previously discussed for abdominal adipose tissue distribution, that serum LDL-C level increases with increasing age both in the normal population and in GHD adults. The reduction of waist circumference, waist:hip ratio, and serum LDL-C level after 2 years were seen only in the elderly GHD patients and these changes were significantly larger than in the younger group. These differences remained after correction for the longer duration of hypopituitarism in the elderly patients. These findings therefore suggest that the elderly GHD patients had the greatest improvement of abdominal fat massand serum lipid pattern, which eliminated the baseline differences in these variables. Femur neck t-score was, as expected based on their increased age, lower in the elderly GHD patients. After correction for age and gender by using z-score, there was instead a non-significant tendency to a higher mean value in the elderly patients. Mean z-score values at all the skeletal sites measured were approximately zero in the elderly GHD patients. This finding is in line with previous studies showing that age- and gender-corrected BMD in elderly GHD patients is not, or only marginally, affected by the hypopituitary disease (5, 6). BMC at the femur neck was, however, lower in the elderly GHD group at baseline. The biological relevance of this finding is not clear, but the possibility can not be excluded that a lower femur neck BMC is of importance for the mechanical strength at this skeletal site, which consists mainly of GH-sensitive cortical bone (24). The incidence of fractures is increased in GHD adults of various ages (25-27), but fracture frequency has not been studied specifically in elderly GHD patients. Prospective studies are therefore needed to explore whether fracture incidence is increased in elderly GHD patients as compared with an age-matched reference population.
There was no significant deterioration of glucose homeostasis in the study groups and no patient developed diabetes mellitus. Insulin sensitivity could be a concern in elderly GHD adults since they may be expected to have lower insulin sensitivity at baseline. This study clearly demonstrates that individualized, low dose GH therapy in elderly GHD adults can produce beneficial results in body composition and serum lipid profile without any significant impairment of glucose metabolism.
The effects of GH replacement on body composition and metabolism were beneficial in the elderly GHD patients, and the reductions in central fat and serum LDL-C level were larger than in the younger patients, thereby eliminating the baseline difference in these variables between the two study groups. There is a possibility that the changes seen in elderly hypopituitary patients were due to regression to the mean, and our findings may also be consistent with the tendency for most treatments (like statins (28)) to be more effective in terms of absolute response, when administered to patients with more severe metabolic deviations at baseline. The changes observed in the elderly GHD patients in this study are, however, opposite of the changes seen during normal aging. Therefore, it appears that GH replacement in hypopituitary patients can at least partly reverse age-related changes in some variables. In this study, the titration of the dose of GH was performed with the aim of normalizing IGF-I SD score. Therefore, in the elderly GHD patients, the GH replacement increased serum IGF-I concentration to that expected in normal elderly subjects. In previous short-term studies in normal elderly subjects, the dose of GH has most often been relatively high, aiming at increasing serum IGF-I concentration to that seen in normal young adults (29, 30). In the study by Blackman et al. (29), the mean dose of GH was approximately 9-10 µg/kg per day and in the study by Lange et al. (30), the final dose of GH was 7.2 µg/kg per day. Although the GH treatment affected body composition and serum lipid pattern also in the normal elderly subjects, there was a relatively high frequency of fluid-related side-effects (29, 30). In the present study, the final dose in the elderly GHD patients was considerably lower (0.31 mg/day; approximately 3.8 µg/kg per day). Although the aim of the GH dose
titration differed between the present study in elderly GHD patients and the previous studies in normal elderly subjects, there is a need for further studies to determine whether long-term, low-dose GH treatment can produce similarly beneficial effects in normal elderly subjects as in hypopituitary patients with few side-effects.
In conclusion, this study shows that elderly patients with GHD, in similarity with the normal aging, have increased central adiposity and increased serum LDL-C level. Lean and bone mass were, however, not different from that in the normal population. The younger GHD patients had, due to the higher dose of GH in this study group, a larger change in IGF-I SD score, total body fat, and extracellular water whereas the improvement of waist:hip ratio and serum lipid pattern was only observed in the elderly GHD patients. These effects were achieved with a small dose of GH that did not significantly affect glucose homeostasis. GH replacement therapy should therefore be considered also in elderly GHD patients.
Acknowledgements
We are indebted to Lena Wirén, Ingrid Hansson and Sigrid Lindstrand at the Research Centre for Endocrinology and Metabolism for their skillful technical support. The study received support from the Sahlgrenska Academy, University of Göteborg and NovoNordisk Scandinavia.
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24.Ohlsson C, Bengtsson B-Å, Isaksson O, Andreassen T, Slootweg M 1998 Growth hormone and bone. Endocr Rev 19:55-79
25.Wüster C, Slenczka E, Ziegler R 1991 Increased prevalence of osteoporosis and arteriosclerosis in conventionally substituted anterior pituitary insufficiency: need for additional growth hormone substitution? Klinische Wochenschrift 69:769-773
26.Rosén T, Wilhelmsen L, Landin-Wilhelmsen K, Lappas G, Bengtsson B-Å 1997 Increased fracture frequency in adult patients with hypopituitarism and GH deficiency. Eur J Endocrinol 137:240-245
27.Wüster C, Abs R, Bengtsson B-Å, Bennmarker H, Feldt-Rasmussen U, Hernberg-Stahl E, Monson JP, Westberg B, Wilton P 2001 The influence of growth hormone deficiency, growth hormone replacement therapy, and other aspects of hypopituitarism on fracture rate and bone mineral density. J Bone Mineral Res16:398-405
28. Heart Protection Study Collaborative Group 2002 MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 360:7-22
29.Blackman M, Sorkin JD, Munzer T, Bellantoni M, Busby-Whitehead J, Stevens T, Jayme J, O'Connor K, Christmas C, Tobin J, Stewart K, Cottrell E, St Clair C, Pabst K, Harman S 2002 Growth hormone and sex steroid administration in
healthy aged women and men: a randomized controlled trial. JAMA 288:2282-2292
30. Lange K, Andersen J, Beyer N, Isaksson F, Larsson B, Rasmussen M, Juul A, Bulow J, Kjaer M 2002 GH administration changes myosin heavy chain isoforms in skeletal muscle but does not augment muscle strength or hypertrophy, either alone or combined with resistance exercise training in healthy elderly men. J Clin Endocrinol Metab 87:513-523
Context: The effects of GH replacement in elderly GH deficient (GHD) adults are not well known.
Objective/Design/Patients: In this prospective, single-centre, open-label study, baseline characteristics and the effects of 2-year GH replacement were determined in 24 GHD adults above 65 years of age and in 24 younger GHD patients (mean age
37; range 27-46 years). All patients had adult onset disease and both groups were comparable in terms of number of pituitary hormonal deficiencies, gender, body mass index (BMI), and waist:hip ratio. Duration of hypopituitarism was, however, longer in
the elderly patients.
Results: The mean maintenance dose of GH was 0.31 (SEM 0.03) mg/day in the elderly GHD patients and 0.44 (0.04) mg/day in the younger patients. The less marked response in IGF-I SD score, total body fat and extracellular water in the elderly patients lost significance when the dose of GH were accounted for in the statistical analyses. In spite of the lower dose in the elderly GHD group, these patients had a more marked reduction in waist:hip ratio and serum low density lipoprotein-cholesterol (LDL-C) level, and these differences remained also after correction for duration of hypopituitarism. There was no difference at baseline or in responsiveness in lean mass, bone mineral density and glucose homeostasis.
Conclusions: This study identifies elderly GHD adults as a GH sensitive group in whom a low dose of GH can improve body composition and serum lipid profile without any significant impairment of glucose metabolism. GH replacement should therefore be considered in elderly GHD adults.
Introduction
Growth hormone (GH) secretion declines with increasing age (1, 2). This may be important for the metabolic changes seen in normal aging, such as an increased relative amount of total and visceral fat, and increased low density lipoproteincholesterol (LDL-C) (1, 2). There are, however, distinct differences between normal elderly subjects and elderly GH deficient (GHD) adults with structural hypothalamicpituitary disease. The elderly GHD adults have lower GH secretion (3) and increased total body fat (4) as compared with age-matched healthy subjects whereas there is little difference in lean mass (4) and bone mass (5, 6). GH replacement can normalize most features of adult GHD (7-9). The response to GH replacement may, however, vary in different subgroups of patients depending on the cause and severity of disease (10), as well as on whether the disease was acquired in childhood or adulthood (11). Little is known of the responsiveness to GH replacement in elderly GHD adults. Several studies suggest that GH replacement in elderly GHD patients has similar efficacy as in younger GHD adults in terms of body composition and serum lipid pattern (12, 13), but it is unknown if the magnitude of the changes differs. It has been suggested in some studies that the elderly GHD patients may need a lower dose of GH than younger patients (14) whereas in other studies, it has been suggested that the main effect of GH replacement in elderly patients may be to prevent further age-related decline in variables such as muscle strength (15). In this single-center, prospective study, baseline characteristics were determined in 24 consecutive GHD patients > 65 years of age at study start and compared with those in 24 GHD adults aged 27-46 years. The two groups were matched with regard to gender, BMI, waist circumference, waist/hip ratio, and number of anterior pituitary hormonal deficiencies, and all patients had adult onset GHD. The main purpose was to study between-group differences in the response to 2-year GH replacement therapy in body composition, bone mass, and metabolic indices.
Patients and Methods
Patients: Twenty-four consecutive GHD adults > 65 years of age (mean age 68, range 65-75 years) and 24 younger GHD adults (age 37, range 27-46 years) were included 1992-1997. All patients had adult onset pituitary disease (Table 1). No patient had previously received GH treatment. In both study groups, 20 patients had been treated surgically. Nine and 6 patients had received radiotherapy in the elderly and in the younger patients, respectively. In 44 of the patients, the diagnosis of GHD was based on a peak GH < 3 µg/L during a stimulation test [insulin (n=41), GHRH (n=3), glucagon (n=1)]. In one elderly patient and in two younger patients, all with multiple pituitary hormonal deficiencies, the diagnosis was based on measurements of 24-hour spontaneous GH secretion (n=2) or on a serum IGF-I concentration below - 2 SD (n=1). When required, patients received adequate and stable therapy with glucocorticoids, thyroid hormone, gonadal steroids and desmopressin. However, at entry to the study, 2/9 (22%), and 5/9 (56%) of the estrogen deficient women in the elderly and younger GHD groups, respectively, received estrogen therapy. In 5 patients, GH replacement was discontinued during the study period. Three of these patients were elderly patients [fatal myocardial infarction (n=1), prostate cancer (n=1, this patients had urinary symptoms already before GH replacement was initiated), and lack of compliance (n=1)]. One patient in the younger group discontinued GH replacement due to reoccurrence of pituitary tumor and one patient was lost to follow-up as this patient moved to another part of Sweden. Patients who discontinued GH replacement were, however, retained in the statistical analysis according to the intention-to treat approach used.
Study protocol: This is an ongoing, prospective, open label treatment trial in adult GHD patients. Various brands of recombinant human GH are used in this trial. In 2 patients (one elderly and one younger patient), the initial target dose of GH was 11.9 µg/kg/d (0.25 IU/kg/week). The dose in these 2 patients was gradually lowered and individualized already during the first year of treatment. In the remaining 46 patients, the dose of GH was individualized from the beginning (16). The individualization of the dose of GH was performed with the aim of normalizing IGF-I SD score (target range: 0 - + 2 SD of predicted values) and body composition (to approximately 100% of predicted values as estimated by the four-compartment model) in each patient (16). The use of IGF-I SD scores may result in lower absolute serum IGF-I values in the elderly than in the younger GHD patients during the GH replacement as serum IGF-I concentration declines with increasing age in the normal population (17). In most patients, the titration of the dose of GH was based on the IGF-I SD score. However, in some patients, mainly patients with an IGF-I SD score in the low normal range at baseline, the normalization of body composition was of increasing importance. The initial dose of GH was 0.5 - 1.0 IU (0.17 - 0.33 mg) per day in the patients that received individualized dose titration. Dose adjustments were made by 0.1 - 0.17 mg per day dependent on the injection device being used. According to the study protocol, the dose of GH was to be reduced by half in the event of side-effects that became a burden for the patients. Therefore, the dose of GH was reduced by half due to fluid-related side-effects in the two patients (one elderly and one young GHD patient) that received their initial dose of GH based on body weight. Smaller reductions (0.1-0.17 mg per day) of the dose of GH were made in 14 additional patients (5 elderly and 9 young patients) due to IGF-I SD score values above + 2 SD or due to mild fluid-related side-effects.
At baseline and then after each year of GH treatment, physical and laboratory examinations were performed including measurements of body composition, bone mass, and metabolic indices. Dose titration and safety monitoring were performed every third month during the first year and every sixth month thereafter. Body weight was measured in the morning to the nearest 0.1 kg, and body height was measured barefoot to the nearest 0.01 m. Body mass index (BMI) was calculated as the weight in kilograms divided by the height in meters squared. Waist circumference was measured in the standing position with a flexible plastic tape placed midway between the lower rib margin and the iliac crest, and hip girth was measured at the widest part of the hip. Systolic and diastolic blood pressure were measured after at least 5 minutes of supine rest using the sphygmomanometric cuff method. No effort was made to influence the patients physical activity level during the study period.
Ethical considerations: Informed consent was obtained from all patients. The study was approved by the Ethics Committee at the University of Göteborg and the Swedish Medical Products Agency (Uppsala, Sweden).
Body composition: Dual-energy X-ray absorptiometry (DEXA) (Lunar DPX-L, Lunar Corporation, Madison, Wisconsin, USA; software version 1.3) was used to measure lean body mass (LBM) and body fat (BFDEXA) (18). The relative error for LBM was 1.5%. Body cell mass (BCM), extra cellular water (ECW), and body fat (BF) were estimated using a four-compartment model based on total body potassium (TBK) and total body water (TBW) assessments (19). TBK was assessed using a whole body counter [coefficient of variation (CV) = 2.2%] and TBW was determined by the isotope dilution of tritiated water (CV = 3.2%). Normative values were derived from studies of 476 healthy subjects (19). Individual observed/predicted values ratios could then be calculated for BCM (BCM%), ECW (ECW%) and BF (BF%).
BMC and BMD DEXA (Lunar DPX-L, software version 1.3) was used to measure BMC and BMD (18). A calibration phantom (COMAC-BME Quantitative Assessment of Osteoporosis Study Group) was used. The CVs between measurements were 0.4%, 0.5%, and 0.6% for total body, lumbar (L2-L4) spine, and femur neck BMD. BMD z-score, which is the difference in SD of age- and sex-matched healthy subjects, and t-score, which is the difference in SD of sex-matched young (20-39-yr-old) healthy subjects, were determined using the Lunar DPX-L software program.
Biochemical assays: Serum IGF-I concentration was determined by a hydrochloric acid-ethanol extraction radioimmunoassay (RIA) (Nichols Institute Diagnostics, San Juan Capistrano, CA). Inter-assay and intra-assay CVs were 5.4 and 6.9%, respectively, at a mean serum IGF-I level of 126 µg/L, and 4.6 and 4.7%, respectively, at mean serum IGF-I level of 327 µg/L. The individual serum IGF-I values were compared with age- and sexadjusted values obtained from a reference population of 197 men and 195 women (17). The individual IGF-I SD scores could then be calculated (20). Serum osteocalcin was measured by a double-antibody RIA (International CIS, GiFsur Yvette, France) with inter-assay and intra-assay CVs of 2.4 and 2.9%, respectively, at a serum concentration of 10.4 ug/L, and 3.3 and 2.9%, respectively, at a mean serum concentration of 22.3 ug/L. Serum calcium was measured by absorption spectrophotometry (Boehringer Mannheim, Mannheim, Germany) with an inter-assay CV of 2.5% and an intra-assay CV of 1.7%. Intact PTH was measured by immunoradiometric assay (Nichols Institute Diagnostics) with inter-assay and intra8 assay CVs of 7.8 and 7.4% at a mean serum concentration of 23.4 ng/L, and 6.0% and 4.5%, respectively, at serum concentration of 43.1 ng/L. Total cholesterol (TC) and triglyceride (TG) concentrations were determined using enzymatic methods (Boehringer Mannheim). The inter-assay CVs for TC and TG determinations were 2.9% and 3.8%, respectively, and intra-assay CVs were 0.9% and 1.1%, respectively. High density lipoprotein (HDL-C) levels were determined after the precipitation of apolipoprotein B - containing lipoproteins with MgCl2 and heparin (21). Low density lipoprotein cholesterol (LDL-C) was calculated according to Friedewald's formula adjusted to SI units (22). Serum insulin was determined by RIA (Phadebas, Pharmacia, Sweden) and blood glucose was measured with the glucose-6-phosphate dehydrogenase method (Kebo Lab, Stockholm, Sweden). Serum HbA1c was determined by high-pressure liquid chromatography (Waters, Millipore AB, Sweden).
Statistical methods
All the descriptive statistical results are presented as the mean and SEM. Betweengroup differences during the 2-year treatment period were determined using a oneway analysis of variance (ANOVA) of the percent change from baseline at all time points, and with onset category as the independent variable. Between-group p-values at baseline and at study end were determined using one-way ANOVA. Within-group p-values were determined using a one-way ANOVA followed by Student-Newman-Keuls post hoc test. All analyses were performed according to the intention-to-treat principle (using the carry forward principle). A two-tailed P < 0.05 was considered significant.
Results
Baseline characteristics (Table 1) Both study groups consisted of 15 men and 9 women (Table 1). The two groups were comparable in terms of gender, body length, body weight, BMI, waist circumference, waist:hip ratio, and number of anterior pituitary hormonal deficiencies (Table 1). There was, however, a non-significant tendency for the younger GHD patients to be taller and heavier and that the elderly patients had larger waist:hip ratios. Furthermore, duration of hypopituitarism was longer in the elderly GHD group (Table 1). GH dose and serum IGF-I (Fig. 1) The daily dose of GH was lower in the elderly GHD patients throughout the 2-year follow-up (Fig. 1A). Serum IGF-I level was lower in the elderly patients throughout treatment (Fig 1B). The serum IGF-I SD score (adjustment for age and gender) tended, however, to be higher in the elderly GHD adults (p=0.16) at baseline (Fig. 1C). There was no significant between-group difference in the percent change in absolute serum IGF-I level whereas the change in IGF-I SD score was smaller in the elderly than in the younger GHD adults (Fig. 1). BMI, waist; hip ratio and blood pressure (Table 2) There was no change during the study period in either group in body weight. Waist circumference and waist:hip ratio reduced more markedly in the elderly GHD group. Systolic and diastolic blood pressures were higher in the elderly GHD group throughout treatment. Although transient reductions in systolic and diastolic blood pressure were observed in the elderly GHD patients after one year of treatment, there was no significant between-group difference.
Body composition (Table 3 and Fig. 2) At baseline, there was no difference in absolute values of measures of body composition except for a lower body cell mass, as measured using the fourcompartment model, in the elderly GHD patients (Table 3). If body composition values were expressed as a percentage of body weight, however, baseline fat and lean mass (including body cell mass) were similar in the two study groups (data not shown). After correction for age and gender using observed/predicted values ratios (four-compartment model), the elderly GHD patients had lower baseline body fat (% of predicted) than the younger GHD patients (Fig 2). The responsiveness to GH replacement in fat and lean mass, both in terms of absolute values (Table 3) or percentages of body weight (data not shown), was similar in the two groups. Body fat (observed/predicted values ratios) was, however, less affected by GH replacement in the elderly GHD patients (Fig. 2). Extracellular water, both expressed as absolute values and as observed/predicted values ratios, was less affected by treatment in the elderly GHD adults (Table 3 and Fig. 2).
Bone markers, BMC, and BMD (data not shown) There was no baseline difference in circulating markers of bone turnover (osteocalcin, calcium, and intact PTH). Within both study groups, circulating osteocalcin and calcium levels were increased by the GH replacement whereas serum intact PTH level was unaffected within both groups. There was, however, no between-group difference in the response to treatment (data not shown). Baseline total body or lumbar (L2-L4) spine BMC, BMD, t-score and z-score was not statistically different between the two groups (data not shown). There was, however, non-significant tendencies to lower total body BMD [1.15 (0.03) vs. 1.20 (0.02) g/cm2], lumbar (L2-L4) spine BMD [1.08 (0.07) vs. 1.18 (0.03) g/cm2], and total body and lumbar (L2-L4) spine t-scores (not shown) in the elderly than in the younger patients. Total body and lumbar (L2-L4) spine z-scores, however, tended to be higher in the elderly GHD patients and were approximately that predicted in the background population (z-score ˜ 0) in this group [mean (SEM) total body and lumbar (L2-L4) spine z-scores in the elderly GHD group were -0.02 (0.24) and 0.06 (0.26), respectively, both p=N.S. vs. the young group]. At the femur neck, BMC [4.46 (0.33) vs. 5.31 (0.18) g; p<0.05], BMD [0.84 (0.05) vs. 1.02 (0.02) g/cm2; p<0.001], and tscore (data not shown, p<0.001) were lower in the elderly than in the younger patients, whereas there was a weak tendency to higher femur neck z-score in the elderly than in the younger GHD group [-0.07 (0.22) vs. -0.21 (0.16); p=N.S.]. There was no within- or between-group difference in the response to 2-year GH replacement in any variable reflecting bone mass and density.
Metabolic analyses (Table 4) At baseline, serum LDL-C concentrations were higher in the elderly GHD adults whereas circulating levels of TC, HDL-C, TG, glucose, insulin, and HbA1c were similar in both groups. A reduction in serum LDL-C level, and a tendency to a reduction in serum TC level, were only found in the elderly GHD adults (p<0.05 and p=0.05, respectively, vs. younger GHD group). There were no within- or betweengroup changes in the other measured metabolic indices.
Analysis of covariance: When the higher dose of GH in the younger GHD patients were accounted for using analysis of covariance, the between-group differences in responsiveness in terms of IGF-I SD score, BF% , ECW, and ECW% lost statistical significance. The more marked reductions in the elderly GHD group in waist:hip ratio, waist circumference and serum LDL-C level all remained also after correction for the longer duration of hypopituitarism in the elderly patients (p<0.05, p<0.01 and p<0.05, respectively).
Discussion
In this single-center, prospective study, a low mean dose of GH normalized serum IGF-I concentration and improved body composition in elderly GHD patients without any significant deterioration in glucose homeostasis. The reductions in waist:hip ratio and serum LDL-C concentration were even more marked in the elderly GHD patients than in the younger GHD patients. Therefore, low-dose GH replacement therapy produces beneficial effects also in elderly GHD adults.
In this study, only one patient in each group started GH replacement with a fix dose of GH based on body weight and already within the first year of treatment, the dose was gradually individualized in these two patients. In all other patients, the GH therapy was individualized from study start. Therefore, the results of this study show, in line with some previous observations (14), that individualized GH replacement results in a lower dose of GH in elderly than in younger GHD patients. Furthermore, the elderly GHD patients had lower absolute values of serum IGF-I at baseline than the younger GHD patients whereas after correction for the age-related decline in serum IGF-I concentration using IGF-SD score, there was a non-significant tendency to higher IGF-I SD score in the elderly patients. This confirms previous observations of a greater overlap in serum IGF-I level between GHD adults and normal individuals with increasing age (23). The change in IGF-I SD score in response to GH was less marked in the elderly GHD adults. Although IGF-I SD score was statistically similar in the two study groups after one and two years, the IGF-I SD score values at these timepoints were approximately + 2 SD in the young GHD patients. This, combined with the supranormalization of extracellular water in the younger patients, could suggest that the dose of GH was a little too high in this group.
The between-group differences at baseline were not due to differences in gender distribution, BMI or severity of disease (as estimated by number of anterior pituitary hormonal deficiencies), since the two study groups were comparable with regard to these factors. However, although they had similar BMI, the elderly patients tended to have higher waist circumference and waist:hip ratios. Baseline total body fat (observed/predicted values ratio), was, however, lower in the elderly than in the younger patients. These results demonstrate that the younger subjects had more excess body fat than the elderly whereas the elderly patients had a more marked abdominal/visceral fat distribution. This is not surprising since visceral obesity increases with ageing in the normal population and therefore, increasing age possibly increases the relative amount of abdominal/visceral obesity also in GHD adults. In the elderly GHD patients, body cell mass was approximately that predicted in the background population, which supports previous observations that there is no major abnormality in lean mass in elderly GHD adults (4).
As measured using the four-compartment model, the reduction of body fat (observed/predicted values ratio), and the increase in extracellular water, were less marked in the elderly GHD patients after 2-year GH replacement. After correction for the lower dose of GH in the elderly patients using an analysis of covariance, the difference in responsiveness in total body fat and extracellular water lost statistical significance. This suggests that GH dose-dependently decreased body fat and increased extracellular water in GHD adults independent of age, thereby eliminating the baseline difference in body fat between the two study groups. Extracellular water, was, however, increased to supraphysiological levels in the younger patients, which is in line with a previous report of more marked fluid retention in younger GHD adults in response to GH replacement (14).
At baseline, serum LDL-C level was, as in the normal population, higher in the elderly than in the younger GHD patients. This suggests, as previously discussed for abdominal adipose tissue distribution, that serum LDL-C level increases with increasing age both in the normal population and in GHD adults. The reduction of waist circumference, waist:hip ratio, and serum LDL-C level after 2 years were seen only in the elderly GHD patients and these changes were significantly larger than in the younger group. These differences remained after correction for the longer duration of hypopituitarism in the elderly patients. These findings therefore suggest that the elderly GHD patients had the greatest improvement of abdominal fat massand serum lipid pattern, which eliminated the baseline differences in these variables. Femur neck t-score was, as expected based on their increased age, lower in the elderly GHD patients. After correction for age and gender by using z-score, there was instead a non-significant tendency to a higher mean value in the elderly patients. Mean z-score values at all the skeletal sites measured were approximately zero in the elderly GHD patients. This finding is in line with previous studies showing that age- and gender-corrected BMD in elderly GHD patients is not, or only marginally, affected by the hypopituitary disease (5, 6). BMC at the femur neck was, however, lower in the elderly GHD group at baseline. The biological relevance of this finding is not clear, but the possibility can not be excluded that a lower femur neck BMC is of importance for the mechanical strength at this skeletal site, which consists mainly of GH-sensitive cortical bone (24). The incidence of fractures is increased in GHD adults of various ages (25-27), but fracture frequency has not been studied specifically in elderly GHD patients. Prospective studies are therefore needed to explore whether fracture incidence is increased in elderly GHD patients as compared with an age-matched reference population.
There was no significant deterioration of glucose homeostasis in the study groups and no patient developed diabetes mellitus. Insulin sensitivity could be a concern in elderly GHD adults since they may be expected to have lower insulin sensitivity at baseline. This study clearly demonstrates that individualized, low dose GH therapy in elderly GHD adults can produce beneficial results in body composition and serum lipid profile without any significant impairment of glucose metabolism.
The effects of GH replacement on body composition and metabolism were beneficial in the elderly GHD patients, and the reductions in central fat and serum LDL-C level were larger than in the younger patients, thereby eliminating the baseline difference in these variables between the two study groups. There is a possibility that the changes seen in elderly hypopituitary patients were due to regression to the mean, and our findings may also be consistent with the tendency for most treatments (like statins (28)) to be more effective in terms of absolute response, when administered to patients with more severe metabolic deviations at baseline. The changes observed in the elderly GHD patients in this study are, however, opposite of the changes seen during normal aging. Therefore, it appears that GH replacement in hypopituitary patients can at least partly reverse age-related changes in some variables. In this study, the titration of the dose of GH was performed with the aim of normalizing IGF-I SD score. Therefore, in the elderly GHD patients, the GH replacement increased serum IGF-I concentration to that expected in normal elderly subjects. In previous short-term studies in normal elderly subjects, the dose of GH has most often been relatively high, aiming at increasing serum IGF-I concentration to that seen in normal young adults (29, 30). In the study by Blackman et al. (29), the mean dose of GH was approximately 9-10 µg/kg per day and in the study by Lange et al. (30), the final dose of GH was 7.2 µg/kg per day. Although the GH treatment affected body composition and serum lipid pattern also in the normal elderly subjects, there was a relatively high frequency of fluid-related side-effects (29, 30). In the present study, the final dose in the elderly GHD patients was considerably lower (0.31 mg/day; approximately 3.8 µg/kg per day). Although the aim of the GH dose
titration differed between the present study in elderly GHD patients and the previous studies in normal elderly subjects, there is a need for further studies to determine whether long-term, low-dose GH treatment can produce similarly beneficial effects in normal elderly subjects as in hypopituitary patients with few side-effects.
In conclusion, this study shows that elderly patients with GHD, in similarity with the normal aging, have increased central adiposity and increased serum LDL-C level. Lean and bone mass were, however, not different from that in the normal population. The younger GHD patients had, due to the higher dose of GH in this study group, a larger change in IGF-I SD score, total body fat, and extracellular water whereas the improvement of waist:hip ratio and serum lipid pattern was only observed in the elderly GHD patients. These effects were achieved with a small dose of GH that did not significantly affect glucose homeostasis. GH replacement therapy should therefore be considered also in elderly GHD patients.
Acknowledgements
We are indebted to Lena Wirén, Ingrid Hansson and Sigrid Lindstrand at the Research Centre for Endocrinology and Metabolism for their skillful technical support. The study received support from the Sahlgrenska Academy, University of Göteborg and NovoNordisk Scandinavia.
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25.Wüster C, Slenczka E, Ziegler R 1991 Increased prevalence of osteoporosis and arteriosclerosis in conventionally substituted anterior pituitary insufficiency: need for additional growth hormone substitution? Klinische Wochenschrift 69:769-773
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No claim or opinion on the SLO Aging Institute web site is intended to be, or should be construed to be, medical advice. Please consult with a healthcare professional before starting any therapeutic program.
No claim or opinion on the SLO Aging Institute web site is intended to be, or should be construed to be, medical advice. Please consult with a healthcare professional before starting any therapeutic program.
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2007 Copyright SLO Aging Institute
2007 Copyright SLO Aging Institute
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Mesotherapy
Facial or Neck Rejuvenation
Cellulite Treatments
Lipotherapy
Body Sculpting
Facial Fillers
Restylane
Radiesse
Hormone Therapy
Human Growth Hormone
Benefits of HGH
Testosterone Replacement
Benefits
Side effects of low testosterone
Women and Hormone Replacement
Thyroid
Supplements and Vitamins
In the News
Zone Type Diet
Body Composition Analysis